It has recently been shown that tumours may be treated selectively through the use of prodrugs, these prodrugs being inactive until metabolised by enzymes expressed by the host. This method of treating cancers is promising, as it allows a greater amount of active agent to be used while reducing systemic side effects.
This type of treatment has been proposed as having potential for the treatment of malignant melanoma, in particular when utilising prodrugs which are effectively recognised by the enzyme tyrosinase. When tyrosinase acts upon the prodrug, an active antitumour agent is released.
In adults, tyrosinase is specifically produced in melanocytes, cells which are responsible for pigmentation. When a patient suffers from melanoma the cancerous cells display a heightened level of tyrosinase. Thus, by employing a prodrug which is specifically recognised by tyrosinase, the prodrug can show greater selectivity for the cancerous cells.
Thus, our International Application No. PCT/GB97/03433 discloses novel prodrugs and assay reagents which are useful as therapeutic agents. These prodrugs and assay reagents were described as being substrates for tyrosinase and of being capable of releasing a therapeutically active agent at a desired location. In particular, a compound called “Prodrug A” is disclosed. Prodrug A has certain drawbacks that make it less than ideal as viable drug for use in the treatment of melanoma. Thus, Prodrug A, although being a substrate for tyrosinase, is also a substrate for other enzymes present in the body. Furthermore, tests have shown Prodrug A to be relatively unstable in solution.
Hong et al. in Journal of Medicinal Chemistry, 1973, Vol. 16, No. 2, p139–147 disclose naturally-occurring 6-ureidopurines and the nucleosides. These compounds show cytokinin and growth inhibitory activity, but have not been shown to have activity on melanoma cells.
U.S. Pat. No. 4,115,539 relates to tyrosine derivatives which may be coupled with other compounds to form derivatives receptive to tagging, e.g. by radiolabeling. The derivatives are useful in detecting compounds of interest in nano- or even pico-molar amounts. In one such compound, tyrosine is coupled to digoxin via a carbamate linker. The disclosed compounds are stated to be useful in analysis techniques, but are not disclosed to have any therapeutic applications, far less to be potential candidates for prodrug treatment of melanoma.
European Application No. 0 583 552 relates to conjugates of chlorophyll and bacteriochlorophyll which are useful as photosensitizers in the diagnosis and therapy of tumours. The chlorophyll and bacteriochlorophyll moieties are conjugated with cell-specific ligands such as hormones, growth factors or tumour-specific antibodies to facilitate targeting the tumour site.
It is an aim of the present invention to provide improved prodrugs for use in the treatment of melanoma. It is a further object of the invention to provide prodrugs which avoid problems associated with prior art prodrugs, specifically which show improved stability and increased selectivity. Thus, it has been found that compared to Prodrug A, compounds which incorporate a urea linkage are advantageous. Prodrug A has a carbamate linkage between the therapeutically active entity and the entity that is recognised by the tyrosinase enzyme. Further, a class of compounds which have only a single hydroxy substituent in the para position have been found to be excellent substrates for tyrosinase enzymes, and to have high specificity.